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Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

ABSTRACT: Short-course preoperative radiotherapy (RT) is widely used in northern Europe for locally advanced resectable rectal cancer, but its role in the era of advanced imaging techniques is uncertain. Here, we reviewed articles and abstracts on SCRT published from 1974 through 2013 with the goal of identifying patients who might be best suited for short-course RT. We included relevant articles comparing surgery with or without preoperative radiation published before and after the advent of total mesorectal excision. We also analyzed two randomized trials directly comparing short-course RT with conventionally fractionated chemoradiation (the Polish Colorectal Study Group and the Trans-Tasman Radiation Oncology Group) that compared short-course RT with conventional chemoradiotherapy. We conclude from our review that short-course RT can be generally applied for operable rectal cancer and produces high rates of pelvic control with acceptable toxicity; it reduces local recurrence rates but does not increase overall survival. SCRT seems to be best used for tumors considered "low risk," i.e., those that are >5 cm from the anal margin, without circumferential margin involvement, and involvement of fewer than 4 lymph nodes. Whether sequential chemotherapy can further improve outcomes remains to be seen, as does the best time for surgery (immediately or 6-8 weeks after RT). We further recommend that selection of patients for short-course RT should be based on findings from magnetic resonance imaging or transrectal ultrasonography.

SUBMITTER: Ciria JP

PROVIDER: S-EPMC4268599 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

Ciria Juan Pablo JP Eguiguren Mikel M Cafiero Sergio S Uranga Intza I Diaz de Cerio Ivan I Querejeta Arrate A Urraca Jose Maria JM Minguez Julian J Guimon Elena E Puertolas Jose Ramón JR

Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology 20140726 1

Short-course preoperative radiotherapy (RT) is widely used in northern Europe for locally advanced resectable rectal cancer, but its role in the era of advanced imaging techniques is uncertain. Here, we reviewed articles and abstracts on SCRT published from 1974 through 2013 with the goal of identifying patients who might be best suited for short-course RT. We included relevant articles comparing surgery with or without preoperative radiation published before and after the advent of total mesore ...[more]

PMID: 25535578

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Project description:BACKGROUND: The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (LARC) dramatically. But a major achievement has been the development of total mesorectal excision (TME) as a surgical standard and the recognition that the surgeon is the predominant prognostic factor. The benefit of preoperative hypofractionated radiotherapy (SCRT; five fractions each of 5 Gy), initially established by the Swedish Rectal Cancer Trial, has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group. The concept of combined neoadjuvant radiochemotherapy (conventional radiation of about 50 Gy with chemotherapy) has not been compared over surgery alone with TME. However, the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy (RCT) was better than postoperative radiochemotherapy in terms of local control. METHODS AND DESIGN: Patients with histological proven rectal cancer staged T2N+ or T3 are randomized to receive either SCRT (25 Gy in five fractions of 5 Gy) plus TME-surgery within 5 days or RCT (50.4 Gy in 28 fractions of 1.8 Gy, continuous infusion 5-fluorouracil) plus TME-surgery 4-6 weeks later. All patients receive adjuvant chemotherapy (12 weeks continuous infusional 5-FU) and are followed up for 5 years. TME-quality is independently documented by the surgeon and the pathologist. Hypothesis of the study is that RCT is superior to SCRT in terms of local recurrence after five years. Secondary endpoints are overall survival, disease-free survival, complete resection rate (R0 resection), rate of sphincter saving resection, acute and late toxicity (radiation related side effects), and quality of life (including long term bowel function). DISCUSSION: Similar long-term survival, local control and late morbidity have been reported for both concepts of preoperative therapy in non-comparative studies. In addition to other ongoing (and recently published) comparative trials we include a larger number of patients for adequate power, apply quality-controlled TME and try to avoid the adjuvant treatment bias by mandatory adjuvant chemotherapy in both groups. Further more, stratification of the initially planned surgical procedure and sphincter-preservation will generate valid evidence whether RCT will allow a less aggressive (sphincter saving) surgical approach.

Project description:Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target.Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT.This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28.ClinicalTrials.gov number, NCT01898104.

Project description:Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life.Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer.ClinicalTrials.gov NCT01558921.

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Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

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Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

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